Cohort study into the neural correlates of postoperative delirium: the role of connectivity and slow-wave activity

Abstract

Background: Delirium frequently affects older patients, increasing morbidity and mortality; however, the pathogenesis is poorly understood. Herein, we tested the cognitive disintegration model, which proposes that a breakdown in frontoparietal connectivity, provoked by increased slow-wave activity (SWA), causes delirium.

Methods: We recruited 70 surgical patients to have preoperative and postoperative cognitive testing, EEG, blood biomarkers, and preoperative MRI. To provide evidence for causality, any putative mechanism had to differentiate on the diagnosis of delirium; change proportionally to delirium severity; and correlate with a known precipitant for delirium, inflammation. Analyses were adjusted for multiple corrections (MCs) where appropriate.

Results: In the preoperative period, subjects who subsequently incurred postoperative delirium had higher alpha power, increased alpha band connectivity (MC P<0.05), but impaired structural connectivity (increased radial diffusivity; MC P<0.05) on diffusion tensor imaging. These connectivity effects were correlated (r2=0.491; P=0.0012). Postoperatively, local SWA over frontal cortex was insufficient to cause delirium. Rather, delirium was associated with increased SWA involving occipitoparietal and frontal cortex, with an accompanying breakdown in functional connectivity. Changes in connectivity correlated with SWA (r2=0.257; P<0.0001), delirium severity rating (r2=0.195; P<0.001), interleukin 10 (r2=0.152; P=0.008), and monocyte chemoattractant protein 1 (r2=0.253; P<0.001).

Conclusions: Whilst frontal SWA occurs in all postoperative patients, delirium results when SWA progresses to involve posterior brain regions, with an associated reduction in connectivity in most subjects. Modifying SWA and connectivity may offer a novel therapeutic approach for delirium.

Clinical trial registration: NCT03124303, NCT02926417.

Keywords: cognitive dysfunction; connectivity; delirium; electroencephalogram; inflammation; mechanism; postoperative; slow wave activity; surgery.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Figures

Fig 1

Study design and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) diagram. (a) Study design. Delirium severity (DRS) is collected during both preoperative and postoperative delirium assessment. (b) STROBE diagram. Data are from IPOD-B2 and IPOD-B3 ongoing perioperative cohort studies. DRS, Delirium Rating of Severity-98; DTI, diffusion tensor imaging; IPOD-B2, Interventions for Postoperative Delirium: Biomarker-2; IPOD-B3, Interventions for Postoperative Delirium: Biomarker-3.

Fig 2

Delirium occurs with increased global slow-wave activity and loss of posterior high-frequency activity. (a) Representative EEG signals from two electrodes, one frontal (Fz) and one posterior/occipital (Oz), collected preoperatively (Preop/Pre) and postoperatively (Post). (b) Group-level spectral analysis comparing patients preoperatively and postoperatively for patients who do (D), or do not (ND), incur delirium (P<0.05 [black squares], linear mixed-effects model across delirium status and operative phase). Spectra range from 0.5 to 40 Hz, statistics were completed for frequency bands; δ 0.5–4 Hz, θ 4–6 Hz, α 6–12 Hz, β 12–28 Hz, γ 28–40 Hz. The alpha band range (α), 6–12 Hz, was chosen by inspecting the peak in the mean spectra amongst all subjects. Topological spectral power of the preoperative and postoperative states for patients who do not incur delirium (c) or do incur delirium (d) across each power band. The third row shows the postoperative>preoperative contrast t-maps, corrected with threshold-free cluster enhancement (TFCE), with overlaid electrodes showing significant differences (statistical non-parametric mapping [SNPM] paired; corrected TFCE P<0.05 [white dots]). (e) Spectral analysis for the transition in state (postoperatively-preoperatively) for subjects who incur delirium or do not (P<0.05 [black squares] after FDR correction with two-sided rank-sum test) for electrodes Fz and Oz. Grey square: uncorrected P<0.05. (f) Topological contrasts of the transition to the non-delirious vs delirious state (first two rows). Third row shows the TFCE t-map of two groups contrast with significant electrodes overlaid (SNPM unpaired; TFCE corrected P<0.05 t-map). For all statistics, nND=48 and nD=22. PSD, power spectral density.

Fig 3

Posterior slow-wave activity (SWA) is associated with (a) delirium severity and (b, c) systemic inflammation. Each column represents the correlation of change in power (postoperatively-preoperatively) with an outcome either Delirium Rating of Severity-98 (DRS), interleukin (IL)-10, or monocyte chemoattractant protein 1 (MCP-1). Top row shows correlation with transition in spectral power across frequencies from occipital electrode (Oz). Spectra range from 0.5 to 40 Hz; statistics done on frequency bands; δ 0.5–4 Hz, θ 4–6 Hz, α 6–12 Hz, β 12–28 Hz, and γ 28–40 Hz. Black square: P<0.05 after false discovery rate correction. Grey square: P<0.05 uncorrected. Middle row shows topological correlation with the increase in SWA (0.5–6 Hz; statistical non-parametric mapping correlation; corrected threshold-free cluster enhancement P<0.05 [white dots show statistically significant electrodes]). Bottom row shows correlation with transition in SWA from occipital electrode Oz. DRS n=70; IL-8 n=47; IL-10 n=46; MCP-1 n=47.

Fig 4

Delirium is associated with decreased connectivity (debiased weighted phase lag index [PLI]). (a) PLI spectral analysis comparing patients preoperatively (pre) and postoperatively (post) for patients who do (D), or do not (ND), incur delirium (P<0.05 [black squares]). Statistical analysis using a linear mixed-effects model across delirium states and pre-/postoperation is reported (nND=48 and nD=22). Spectra range from 0.5 to 40 Hz; statistics done on frequency bands; δ 0.5–4 Hz, θ 4–6 Hz, α 6–12 Hz, β 12–28 Hz, and γ 28–40 Hz. (b) Topologically PLI of preoperative and postoperative states for patients who do not, or do, incur delirium. PLI with a frontal square group of electrodes is displayed and corrected. Bottom row shows postoperative>preoperative contrast (P<0.05 [line displayed if significant] after false discovery rate (FDR) correction with two-sided Wilcoxon signed-rank test). Right column shows contrast between patients who do, and do not, incur delirium, delirium>no delirium (P<0.05 after FDR correction with two-sided Wilcoxon rank-sum test; nND=48 and nD=22). (c) Topological plots of the change in connectivity with transition to the non-delirious vs delirious state. Right, topoplot shows threshold-free cluster enhancement t-map of two groups contrast (P<0.05 after FDR correction with two-sided Wilcoxon rank-sum test; nND=48 and nD=22). (d) Correlation of the postoperative–preoperative difference in PLI with changes in Delirium Rating of Severity-98 (DRS), interleukin (IL)-10, monocyte chemoattractant protein 1 (MCP-1), and slow-wave activity (SWA). Left column shows r2 map (P<0.05 after FDR correction; DRS n=70 [64–69, after outlier exclusion], IL-10 n=46 [42–45], MCP-1 n=47 [42–46], and SWA n=70 [63–68]). Right columns show correlations with PLI of frontal square connecting to square below.

Fig 5

Preoperative connectivity is increased before delirium and inversely correlates with structural connectivity. (a) Preoperative radial diffusivity (RD) contrast for patients who do not incur delirium (ND) and do incur delirium (D) (general linear model with covariate age+gender; P<0.05 family-wise error corrected; nND=51 and nD=17). Significant effects of RD (red) are overlaid on whole brain white matter tract (green). The right box plot shows mean RD contrast across significant voxels detected with multiple comparison correction between the groups (P<0.05 corrected; two-sided Wilcoxon rank-sum test). (b) Correlation of preoperative RD with peak postoperative delirium severity (general linear model with covariate age+gender; P<0.05 FWE corrected; n=68). (c) Correlation of preoperative (preop) topological alpha phase lag index (PLI) and mean RD across significant voxels (P<0.05 after false discovery rate correction; n=36 [33–36 after outlier exclusion]). Left, topoplot shows r2 map for the PLI of frontal square is displayed and corrected. Right plot shows mean RD correlation with PLI of frontal square connecting to parietal square. DRS, Delirium Rating of Severity-98.